Extended release liquid compositions of guanfacine

ABSTRACT

The present invention relates to extended release liquid compositions of guanfacine. The extended release liquid compositions of the present invention are bioequivalent to marketed extended release tablet compositions of guanfacine. Said extended release liquid compositions provide substantially similar in-vitro dissolution release profile upon storage for at least seven days. Further, the extended release liquid compositions are stable. The extended release liquid compositions are in the form of ready-to-use liquid compositions or reconstituted liquid compositions. It also relates to processes for the preparation of said extended release liquid compositions.

FIELD OF THE INVENTION

The present invention relates to extended release liquid compositions ofguanfacine. The extended release liquid compositions of the presentinvention are bioequivalent to marketed extended release tabletcompositions of guanfacine. Said extended release liquid compositionsprovide substantially similar in-vitro dissolution release profile uponstorage for at least seven days. Further, the extended release liquidcompositions are stable. The extended release liquid compositions are inthe form of ready-to-use liquid compositions or reconstituted liquidcompositions. It also relates to processes for the preparation of saidextended release liquid compositions.

BACKGROUND OF THE INVENTION

Guanfacine is a central alpha_(2A)-adrenergic receptor agonist indicatedfor the treatment of Attention Deficit Hyperactivity Disorder (ADHD) asa monotherapy and as an adjunctive therapy to stimulant medications.Guanfacine hydrochloride, a pharmaceutically acceptable salt ofguanfacine, is a white to off-white crystalline powder, sparinglysoluble in water (approximately 1 mg/mL) and alcohol and slightlysoluble in acetone. The chemical designation for guanfacinehydrochloride is N-amidino-2-(2,6-dichlorophenyl)-acetamidemonohydrochloride. The chemical structure is:

Guanfacine and its pharmaceutically acceptable salts are disclosed inU.S. Pat. No. 3,632,645. U.S. Pat. No. 5,854,290 discloses the method oftreating a behavioral disinhibition (e.g. Attention-DeficitHyperactivity Disorder) in a primate with minimal sedative side effectsby administering thereto a therapeutically effective amount ofguanfacine.

U.S. Pat. No.'s. 6,287,599 and 6,811,794 describe sustained releasetablet compositions of guanfacine, comprising at least one non-pHdependent sustained release agent, and at least one pH dependent agentthat increases the rate of release of guanfacine from the tablet at a pHin excess of 5.5.

Guanfacine is presently marketed only in solid dosage forms i.e.immediate release and extended release tablets for oral administration.However, these solid dosage forms are not suited for patients who havedifficulty in swallowing. Further, solid dosage forms may not beconvenient, when chronic therapy is needed.

Therefore, there exists a need in the art for liquid compositions ofguanfacine for better patient compliance, convenience and doseflexibility. Of particular advantage would be extended release liquidcompositions that can provide effective plasma levels over a prolongedperiod of time. In view of this, extended release liquid compositionsare clearly advantageous over the presently available solid dosageforms.

However, it remains a great challenge to formulate an extended releaseliquid composition of guanfacine. First challenge is to avoid therelease of guanfacine from extended release units into a liquid carrierduring storage, and to release only when the composition enters thegastrointestinal tract. Guanfacine may leach out from the extendedrelease units into the liquid carrier during storage, thus obliteratingthe whole objective of the extended release. Furthermore, the irregularrelease may lead to sub-therapeutic or toxic effects leading to seriousmedical conditions. Another challenge with the liquid composition ofguanfacine is the stability of guanfacine, both during the manufacturingprocess and shelf-life.

The inventors of the present invention have addressed all thesechallenges and have for the first time developed extended release liquidcompositions of guanfacine. The compositions described herein arecapable of providing consistent in-vitro extended release of guanfacinewhich further ensures steady plasma concentrations throughout the shelflife of the compositions. Further, said extended release liquidcompositions provide desired in-vivo release of guanfacine and arebioequivalent to a reference composition. Furthermore, the extendedrelease liquid compositions are stable both during manufacturing andstorage period.

Therefore, the present invention is a significant advance over theavailable solid dosage forms of guanfacine and fulfills the long feltneed to improve patient compliance by providing an extended releaseliquid composition of guanfacine with consistent release and acceptablestability.

The extended release liquid compositions of guanfacine offer additionaladvantages as they are easy to manufacture with functionalreproducibility. The extended release liquid compositions describedherein are provided with a pleasant mouth feel thereby further enhancingpatient compliance and ease of administration.

SUMMARY OF THE INVENTION

The present invention relates to extended release liquid compositions ofguanfacine. The extended release liquid compositions of the presentinvention are bioequivalent to a marketed extended release tablet ofguanfacine. Said compositions provide substantially similar in-vitrodissolution release profile upon storage for at least seven days.Further, the extended release liquid compositions of the presentinvention are stable.

The extended release liquid compositions are in the form of ready-to-useliquid compositions or reconstituted liquid compositions. The extendedrelease liquid compositions offer better patient compliance and dosingflexibility based on age and body weight of the patients. It furtherrelates to processes for the preparation of said extended release liquidcompositions.

DETAILED DESCRIPTION OF THE INVENTION

A first aspect of the present invention provides an extended releaseliquid composition comprising guanfacine in a pharmaceuticallyacceptable carrier.

A second aspect of the present invention provides an extended releaseliquid composition comprising guanfacine in a pharmaceuticallyacceptable carrier, wherein the composition comprises guanfacine in aconcentration from about 0.1 mg/mL to about 12.0 mg/mL of thecomposition.

In a particular embodiment, the composition comprises guanfacine in aconcentration from about 1.0 mg/mL to about 7.0 mg/mL of thecomposition.

A third aspect of the present invention provides an extended releaseliquid composition comprising guanfacine in a pharmaceuticallyacceptable carrier, wherein the extended release liquid composition isbioequivalent to a marketed extended release tablet composition.

According to one embodiment, the composition exhibits an AUC_(0→∞)ranging from about 34000 hr*pg/mL to about 220000 hr*pg/mL uponadministration of a 4 mg dose of guanfacine under fasting state. In aparticular embodiment, the composition exhibits an AUC_(0→∞) rangingfrom about 34000 hr*pg/mL to about 160000 hr*pg/mL upon administrationof a 4 mg dose of guanfacine under fasting state.

According to another embodiment, the composition exhibits an AUC_(last)ranging from about 32000 hr*pg/mL to about 180000 hr*pg/mL uponadministration of a 4 mg dose of guanfacine under fasting state. In aparticular embodiment, the composition exhibits an AUC_(last) rangingfrom about 32000 hr*pg/mL to about 150000 hr*pg/mL upon administrationof a 4 mg dose of guanfacine under fasting state.

According to another embodiment, the composition exhibits a C_(max) fromabout 1800 pg/mL to about 9000 pg/mL upon administration of a 4 mg doseof guanfacine under fasting state. In a particular embodiment, thecomposition exhibits a C_(max) from about 1800 pg/mL to about 4000 pg/mLupon administration of a 4 mg dose of guanfacine under fasting state.

According to another embodiment, the composition exhibits a T_(max) fromabout 2 hours to about 10 hours upon administration of a 4 mg dose ofguanfacine under fasting state.

According to another embodiment, the composition exhibits a T_(lag) ofless than about 2 hours, upon administration of a 4 mg dose ofguanfacine under fasting state.

A fourth aspect of the present invention provides an extended releaseliquid composition comprising guanfacine in a pharmaceuticallyacceptable carrier, wherein the composition is characterized by havingan in-vitro dissolution release profile when determined for a 4 mg doseof 1 mg/mL concentration using USP type II apparatus at 75 rpm, in 900mL of hydrochloric acid buffer with a pH 2.2 at 37° C. as follows:

a. not more than about 30% of guanfacine released after 1 hour;

b. about 35 to about 75% of guanfacine released after 4 hours; and

c. not less than about 75% of guanfacine released after 24 hours.

According to another embodiment, the in-vitro dissolution releaseprofile of the composition upon storage for at least seven days remainssubstantially similar to the initial in-vitro dissolution releaseprofile.

A fifth aspect of the present invention provides an extended releaseliquid composition comprising guanfacine in a pharmaceuticallyacceptable carrier, wherein the composition is a stable composition.Particularly, the composition is stable for at least seven days. Moreparticularly, the composition is stable for at least one month, orfurther, to the extent necessary for the sale and use of thecomposition.

According to another embodiment, the composition comprises less thanabout 1.0% w/w of 2,6-dichlorophenyl acetic acid. Particularly, thecomposition comprises less than about 0.7% w/w of 2,6-dichlorophenylacetic acid.

According to another embodiment, the composition comprises less thanabout 3.0% w/w of total related substances. Particularly, thecomposition comprises less than about 2.0% w/w of total relatedsubstances.

A sixth aspect of the present invention provides an extended releaseliquid composition comprising guanfacine in a pharmaceuticallyacceptable carrier, wherein the composition has a pH of less than about6.8.

A seventh aspect of the present invention provides an extended releaseliquid composition comprising guanfacine in a pharmaceuticallyacceptable carrier, wherein the composition is a ready-to-use liquidcomposition or a reconstituted liquid composition.

According to another embodiment, the ready-to-use liquid compositioncomprises a suspension, a syrup, a concentrate, an elixir or anemulsion.

According to another embodiment, the reconstituted liquid compositioncomprises a suspension reconstituted from dry powder comprisinggranules, pellets, or beads.

According to another embodiment of the above aspects, the composition isa taste-masked composition.

An eighth aspect of the present invention provides an extended releaseliquid composition comprising guanfacine in a pharmaceuticallyacceptable carrier, wherein the composition comprises:

(i) cores comprising guanfacine and a release-controlling agent; and

(ii) a pharmaceutically acceptable carrier.

In one embodiment, guanfacine may be present in the core or layered overan inert particle to form a core.

According to another embodiment, the core is in the form of a bead, apellet, a granule, a spheroid, or the like.

According to another embodiment, the inert particle is selected from agroup comprising a non-pareil seed, a microcrystalline cellulose sphere,a dibasic calcium phosphate bead, a mannitol bead, a silica bead, atartaric acid pellet, or a wax based pellet.

In another embodiment, the release-controlling agent may be present inthe core or coated over the guanfacine core or both.

According to another embodiment, the release-controlling agent isselected from the group comprising a pH-dependent release controllingagent, a pH-independent release controlling agent, or mixtures thereof.

According to another embodiment, the core further comprises otherpharmaceutically acceptable excipients selected from the groupcomprising acids, osmogents, binders, glidants, or combinations thereof.

According to another embodiment, the pharmaceutically acceptable carriercomprises one or more of liquid adjuvants and other pharmaceuticallyacceptable excipients.

According to another embodiment, the other pharmaceutically acceptableexcipients in the carrier are selected from the group comprising acids,osmogents, buffering agents, suspending agents, glidants, sweeteningagents, flavors, colorants, anti-caking agents, wetting agents,preservatives, antioxidants, chelating agents, binders, viscositymodifiers, and combinations thereof.

According to another embodiment of the above aspects, the corescomprising guanfacine and a release-controlling agent have a particlesize d₉₀ value of less than about 1.5 mm.

According to another embodiment of the above aspects, the extendedrelease liquid composition is characterized by having an osmolalityratio of at least about 1.

According to another embodiment of the above aspects, thepharmaceutically acceptable carrier has an osmolality of about 1osmol/kg or more than about 1 osmol/kg of the carrier.

According to another embodiment, the composition further comprisesguanfacine in an immediate release form.

A ninth aspect of the present invention, provides a method of treatingAttention Deficit Hyperactivity Disorder by administering an extendedrelease liquid composition comprising guanfacine in a pharmaceuticallyacceptable carrier.

In an embodiment of the above aspect, the extended release liquidcomposition is administered once daily.

The term “guanfacine,” as used herein, refers to guanfacine, as well asits pharmaceutically acceptable salts, polymorphs, hydrates, solvates,prodrugs, chelates, and complexes. Exemplary salts include salts ofinorganic or organic acids such as hydrochloride, hydrobromide,sulphate, sulfamate, nitrate, phosphate, formate, mesylate, citrate,benzoate, fumarate, maleate, tartrate, and succinate. A particularlypreferred salt of guanfacine is guanfacine hydrochloride.

The extended release liquid composition comprises guanfacine in aconcentration from about 0.1 mg/mL to about 12 mg/mL of the composition.Preferably, the extended release liquid composition comprises guanfacinein a concentration from about 1.0 mg/mL to about 7.0 mg/mL of thecomposition.

As used herein, the term “extended release,” is used to define a releaseprofile to effect delivery of guanfacine over an extended period oftime, as being between about 60 minutes to about 2, 4, 6, 8, 12 or 24hours. The extended release includes sustained release, controlledrelease, multiphase release, delayed release, pulsatile release, chronorelease and the like.

The extended release liquid composition of the present invention isbioequivalent to a reference product. The reference product is anextended release tablet of guanfacine available in strengths of 1 mg, 2mg, 3 mg and 4 mg marketed under the brand name Intuniv® by Shire.

The term “bioequivalent,” as used herein, is a term of art and isdefined to mean the term used by the drug approval agencies, such as theUS Food and Drug Administration: “the absence of a significantdifference in the rate and extent to which the active ingredient oractive moiety in pharmaceutical equivalents or pharmaceuticalalternatives becomes available at the site of drug action whenadministered at the same molar dose under similar conditions in anappropriately designed study.” Bioequivalence of different formulationsof the same drug substance involves equivalence with respect to the rateand extent of drug absorption. Two formulations whose rate and extent ofabsorption differ by −20%/+25% or less are generally considered to bebioequivalent. Detailed guidelines for establishing the bioequivalenceof a formulation with a reference formulation have been published by theFDA Office of Generic Drugs, Division of Bioequivalence. Pharmacokineticparameters such as C_(max), T_(max), AUC_(last) and AUC_(0→∞) are usedto establish bioequivalency.

The term “AUC_(0→∞),” as used herein, refers to the area under theplasma concentration-time curve extrapolated to infinity.

The term “AUC_(last),” as used herein, refers to the area under theplasma concentration-time curve from time 0 up to the time correspondingto the last quantifiable concentration.

The term “C_(max),” as used herein refers to the maximum plasmaconcentration of guanfacine.

The term “T_(max),” as used herein, refers to the time to reach maximumplasma guanfacine concentration of guanfacine.

The term “Lag time (T_(lag)),” as used herein, refers to the timebetween administration of the composition and the first quantifiableplasma level concentration of guanfacine in the plasma concentrationversus time curve.

In the context of the present invention, the pharmacokinetic parametersare calculated as mean values taken from a population of individualsparticipating in the study.

The extended release liquid compositions also provide the consistentin-vivo release which ensures steady and predictable guanfacine releasewith minimal inter and intra subject variation throughout the shelf lifeof the composition.

The in-vitro dissolution release profile of the extended release liquidcompositions upon storage for at least seven days remains substantiallysimilar to the initial in-vitro dissolution release profile obtained assoon as practicable after preparation of the extended release liquidcompositions. Particularly, the in-vitro dissolution release profile ofthe extended release liquid compositions upon storage at roomtemperature for at least one month remains substantially similar to theinitial in-vitro dissolution release profile obtained as soon aspracticable after preparation of the extended release liquidcompositions. More particularly, the in-vitro dissolution releaseprofile of the extended release liquid compositions upon storage at roomtemperature for at least three months remains substantially similar tothe initial in-vitro dissolution release profile obtained as soon aspracticable after preparation of the extended release liquidcompositions. The in-vitro dissolution release profile is measured byusing any known dissolution methods, in particular the in-vitrodissolution release is measured at 37° C. using a USP type II apparatusat 75 rpm, in 900 mL of hydrochloric acid buffer with a pH 2.2.

Guanfacine, particularly guanfacine hydrochloride, is found to degradeat high pH values. Solution state stability studies have indicated thatat 16 hours, assay values of guanfacine have dropped down to 86.3% and84% at pH 6.8 and 7.5 respectively and even further reduced at 24 hours.One of the major impurity of guanfacine is 2,6-dichlorophenyl aceticacid.

Inventors have surprisingly discovered that degradation of guanfacinecan be prevented by maintaining the pH of the composition to less thanabout 6.8. In the present invention, the pH of the reconstituted liquidcomposition or ready-to-use liquid composition implies pH valuesmeasured for the pharmaceutically acceptable carrier, for the coatedcores, or in the microenvironment of guanfacine, or combination of thesethat is sufficient to prevent degradation of guanfacine.

The term “stable,” as used herein, refers to chemical stability, whereinthe amount of impurity 2,6- dichlorophenyl acetic acid in thecomposition remains less than about 1.0% w/w, particularly less thanabout 0.7% w/w upon storage of the composition for a period of at leastseven days, more particularly, for a period of at least one month, orfurther, to the extent necessary for the sale and use of thecomposition.

The extended release liquid composition is in the form of a ready-to-useliquid composition or a reconstituted liquid composition. Theready-to-use liquid composition comprises a suspension, a syrup, aconcentrate, an elixir or an emulsion or like. The reconstituted liquidcomposition comprises a suspension reconstituted in the carrier from drypowder comprising pellets, granules, beads, or the like.

The present invention provides extended release liquid compositioncomprising:

(i) cores comprising guanfacine and a release-controlling agent; and

(ii) a pharmaceutically acceptable carrier.

The term “pharmaceutically acceptable carrier,” as used herein, acts asa suspension base used to suspend the guanfacine cores. Thispharmaceutically acceptable carrier comprises one or more of liquidadjuvants and other pharmaceutically acceptable excipients. When thecomposition is a reconstituted liquid composition, the powder forsuspension comprising cores of guanfacine are reconstituted with thecarrier comprising one or more of liquid adjuvants and otherpharmaceutically acceptable excipients. Alternatively, one or more ofother pharmaceutically acceptable excipients may be mixed with the coresof guanfacine which may then be reconstituted with a liquid adjuvant.The pharmaceutically acceptable carrier may be pre-formed or formed atthe time of reconstitution.

The pharmaceutically acceptable carrier may play a role in creating ahypertonic environment. The term “hypertonic environment,” as usedherein, means that the pharmaceutically acceptable carrier has highersolute concentration which helps to generate high osmotic pressure suchthat there is no leaching of guanfacine from the extended release coatedcores into the carrier.

The term “osmolality,” as used herein, means the number of moles of anywater-soluble compound per kg of the carrier. In the present invention,the osmolality may be measured according to known methods, such as usinga Vapor pressure Osmometer, a Colloid Osmometer, or a Freezing PointDepression Osmometer such as Osmomat® 030-D or Osmomat® 3000, inparticular by a Freezing Point Depression Osmometer. In the presentinvention, pharmaceutically acceptable carrier has an osmolality ofabout 1 osmol/kg or more than about 1 osmol/kg of the pharmaceuticallyacceptable carrier.

The term “osmolality ratio,” as used herein, means the ratio ofosmolality of the external phase to the osmolality of the internalphase. The external phase herein means the carrier without the coatedcores of guanfacine. The internal phase herein means the coated cores ofguanfacine.

As the direct measurement of the osmolality of the internal phase i.e.,coated cores is difficult, the osmolality of the internal phase herein,is represented as the osmolality of a solution which preventssignificant leaching of guanfacine from the coated cores into thesolution. The leaching of guanfacine from the coated cores is determinedby the difference in the osmolalities across the coating layer and theabsence of any significant leaching from the coated cores directs thatthe osmolality of the solution has become equal to the osmolality of thecoated cores. The osmolality ratio of the extended release liquidcompositions of present invention is at least about 1.0.

The osmolality of the carrier remains equivalent upon storage for atleast seven days. Particularly, the osmolality of the carrier measuredafter one month remains equivalent to the osmolality of the carriermeasured as soon as practicable after preparation of the extendedrelease liquid compositions. More particularly, the osmolality of thecarrier measured after three months remains equivalent to the osmolalityof the carrier measured as soon as practicable after preparation of theextended release suspension compositions. More particularly, theosmolality of the carrier measured after three months remainssubstantially similar to the osmolality of the carrier measured as soonas practicable after preparation of the extended release liquidcompositions. The equivalent osmolality of the carrier ensures thatthere is no leaching of the guanfacine from the coated cores intocarrier.

In certain embodiments, the pharmaceutically acceptable carrier in thepresent invention comprises one or more of liquid adjuvants and otherpharmaceutically acceptable excipients.

Suitable liquid adjuvants comprise water. It may optionally comprise aco-solvent, for example, propylene glycol, glycerol, sorbitol, and thelike, to assist solubilization and incorporation of variouswater-insoluble ingredients, such as flavoring oils and the like, intothe composition.

In certain embodiments, other pharmaceutically acceptable excipients inthe carrier are selected from the group comprising acids, osmogents,buffering agents, suspending agents, glidants, sweetening agents,flavors, colorants, anti-caking agents, wetting agents, preservatives,antioxidants, chelating agents, binders, viscosity modifiers, andcombinations thereof.

Suitable acids are selected from the group comprising organic acids,inorganic acids or mixtures thereof. Organic acids are selected from thegroup comprising citric acid, fumaric acid, tartaric acid, oxalic acid,succinic acid, adipic acid, phthalic acid, acetic acid, alginic acid,ascorbic acid, aspartic acid, benzoic acid, cyclamic acid, erythorbicacid, glutamic acid hydrochloride, lactic acid, maleic acid, methacrylicacid, oleic acid, palmitic acid, sorbic acid, stearic acid, andcombinations thereof. Inorganic acids are selected from the groupcomprising hydrochloric acid, hydrobromic acid, hydroiodic acid, nitricacid, phosphoric acid, sulfuric acid, boric acid, perchloric acid, andcombinations thereof. Citric acid, fumaric acid, tartaric acid, ascorbicacid, benzoic acid, and hydrochloric acid are preferably used.

As used herein, the term “osmogents,” refers to all pharmaceuticallyacceptable inert water-soluble compounds that can imbibe or dissolve inwater and/or aqueous biological fluids. Suitable examples of osmogentsor pharmaceutically acceptable inert water-soluble compounds areselected from the group comprising carbohydrates such as xylitol,mannitol, sorbitol, arabinose, ribose, xylose, glucose, fructose,mannose, galactose, sucrose, maltose, lactose, dextrose and raffinose;water-soluble salts of inorganic acids such as magnesium chloride,magnesium sulfate, potassium sulfate, lithium chloride, sodium chloride,potassium chloride, lithium hydrogen phosphate, sodium hydrogenphosphate, potassium hydrogen phosphate, lithium dihydrogen phosphate,sodium dihydrogen phosphate, potassium dihydrogen phosphate, and sodiumphosphate tribasic; water-soluble salts of organic acids such as sodiumacetate, potassium acetate, magnesium succinate, sodium benzoate, sodiumcitrate, and sodium ascorbate; water-soluble amino acids such asglycine, leucine, alanine, methionine; urea or its derivatives;propylene glycol; glycerin; polyethylene oxide, xanthan gum,hydroxypropylmethyl cellulose; and mixtures thereof. Particularly, theosmogents used in the present invention are xylitol, mannitol, glucose,lactose, sucrose, and sodium chloride.

Suitable buffering agents are selected from the group comprisinghydrochloric acid, citric acid, sodium citrate, potassium citrate,acetate, sodium acetate trihydrate, potassium dihydrogen orthophosphate,trisodium hydrogen orthophosphate, sodium dihydrogen orthophosphate,disodium hydrogen orthophosphate, and mixtures thereof.

Suitable suspending agents are selected from the group comprisingcellulose derivatives such as co-processed spray dried forms ofmicrocrystalline cellulose and carboxymethyl cellulose sodium,hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose, methylcellulose, carboxymethyl cellulose and itssalts/derivatives, and microcrystalline cellulose; carbomers; gums suchas locust bean gum, xanthan gum, tragacanth gum, arabinogalactan gum,agar gum, gellan gum, guar gum, apricot gum, karaya gum, sterculia gum,acacia gum, gum arabic, and carrageenan; pectin; dextran; gelatin;polyethylene glycols; polyvinyl compounds such as polyvinyl acetate,polyvinyl alcohol, and polyvinyl pyrrolidone; sugar alcohols such asxylitol and mannitol; colloidal silica; and mixtures thereof. Theco-processed spray dried forms of microcrystalline cellulose andcarboxymethyl cellulose sodium are marketed under the trade namesAvicel® RC-501, Avicel® RC-581, Avicel® RC-591, and Avicel®CL-611.

Suitable glidants are selected from the group comprising silica, calciumsilicate, magnesium silicate, colloidal silicon dioxide, corn starch,talc, stearic acid, magnesium stearate, calcium stearate, sodium stearylfumarate, hydrogenated vegetable, and mixtures thereof.

Suitable sweetening agents are selected from the group comprisingsaccharine or its salts such as sodium, potassium, or calcium, cyclamateor its salt, aspartame, alitame, acesulfame or its salt, stevioside,glycyrrhizin or its derivatives, sucralose, and mixtures thereof.

Suitable flavors are selected from the group comprising peppermint,grapefruit, orange, lime, lemon, mandarin, pineapple, strawberry,raspberry, mango, passion fruit, kiwi, apple, pear, peach, apricot,cherry, grape, banana, cranberry, blueberry, black currant, red currant,gooseberry, lingon berries, cumin, thyme, basil, camille, valerian,fennel, parsley, chamomile, tarragon, lavender, dill, bargamot, salvia,aloe vera balsam, spearmint, eucalyptus, and combinations thereof.

Suitable coloring agents are selected from the group comprising dyes,natural coloring agents or pigments, approved for use under FederalFood, Drug and Cosmetic Act.

Suitable anti-caking agents are selected from the group comprisingcolloidal silicon dioxide, tribasic calcium phosphate, powderedcellulose, magnesium trisilicate, starch, and mixtures thereof.

Suitable wetting agents are selected from the group comprising anionic,cationic, nonionic, or zwitterionic surfactants, and combinationsthereof. Suitable examples of wetting agents are sodium lauryl sulphate;cetrimide; polyethylene glycols; polyoxyethylene-polyoxypropylene blockcopolymers such as poloxamers; polyglycerin fatty acid esters such asdecaglyceryl monolaurate and decaglyceryl monomyristate; sorbitan fattyacid esters such as sorbitan monostearate; polyoxyethylene sorbitanfatty acid ester such as polyoxyethylene sorbitan monooleate;polyethylene glycol fatty acid ester such as polyoxyethylenemonostearate; polyoxyethylene alkyl ether such as polyoxyethylene laurylether; polyoxyethylene castor oil; and mixtures thereof.

Suitable preservatives are selected from the group comprising parabenssuch as methyl, ethyl, propyl, and butyl p-hydroxybenzoic acid esters,alkyl hydroxybenzoates, sorbic acid or a salt thereof, benzoic acid or asalt thereof, salts of edetate (also known as salts ofethylenediaminetetraacetic acid or EDTA, such as disodium edetate),benzalkonium chloride, and mixtures thereof.

Suitable antioxidants are selected from the group comprising butylatedhydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodiummetabisulfite, ascorbic acid, propyl gallate, thiourea, tocopherols,beta-carotene, and mixtures thereof.

Suitable chelating agents are selected from the group comprisingethylenediamine tetraacetic acid (EDTA) and its salts, such as, forexample, dipotassium ethylenediamine tetraacetate, calcium disodiumethylenediamine tetraacetate, tetrasodium ethylenediamine tetraacetate,and mixtures thereof.

Suitable binders are selected from the group comprising polyvinylpyrrolidone, starch, pregelatinized starch, hydroxypropylmethylcellulose, hydroxyethyl cellulose, methyl cellulose, sodiumcarboxymethyl cellulose, gums, acrylate polymers, and mixtures thereof.

Suitable viscosity modifiers are selected from the group comprisingchitosan, acacia, alginic acid bentonite, carbomers,carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methylcellulose, ethylcellulose, glycerin, gelatin guar gum, hydroxyethylcellulose, hydroxymethyl cellulose, hydroxypropyl cellulose,hydroxypropyl methyl cellulose, any other suitable cellulose-basedcomponent, maltodextrin, polyvinyl alcohol, povidone, propylenecarbonate, propylene glycol alginate, sodium alginate, starch, sodiumstarch glycolate, starch tragacanth, and xanthan gum, and mixturesthereof.

The extended release liquid composition may additionally include animmediate release component of guanfacine that can help in providing abiphasic or pulsatile type release. Immediate release component may helpin providing an immediate therapeutic effect which could be subsequentlyfollowed by an extended therapeutic effect over a longer duration oftime. The immediate release guanfacine may be present in the carrier inan amount that is less than the saturation amount. Alternatively, theamount of immediate release guanfacine may be more than the amountneeded to form the saturated solution either initially or during storageof the extended release composition.

This immediate release component may be present in the form of powder,pellets, beads, spheroids or granules of guanfacine. Alternatively, theimmediate release component may be present in the form of an immediaterelease coating of guanfacine over the extended release cores ofguanfacine. Alternatively, the immediate release component of guanfacinemay be present in form of guanfacine-resin complexes.

Cation- and anion-exchange resins are well-known in the art. Fewexemplary resins that can be used according to the invention include,but are not limited to, Dowex® resins and others made by Dow Chemical;Amberlite®, Amberlyst® and other resins made by Rohm and Haas; Indion®resins made by Ion Exchange, Ltd. (India), Diaion® resins by Mitsubishi;Type AG® and other resins by BioRad; Sephadex® and Sepharose® made byAmersham; resins by Lewatit, sold by Fluka; Toyopearl® resins by ToyoSoda; IONAC® and Whatman® resins sold by VWR; and BakerBond® resins soldby J T Baker; hydrophilic colloids such as, e.g., alginate, chitsoan,carboxymethylcellulose, croscarmellose, microcrystalline cellulose,xanthan gum, carboxy vinyl polymers such as carbomer 94, polylysine,gelatin; and resins having polymer backbones comprising styrene-divinylbenzene copolymers and having pendant ammonium or tetraalkyl ammoniumfunctional groups, available from Rohm and Haas, and sold under thetradename DUOLITE™ AP143; or any combinations thereof.

The viscosity of the pharmaceutically acceptable carrier ranges fromabout 300 cps to about 15,000 cps. Preferably, the viscosity of thecarrier ranges from about 500 cps to about 10,000 cps. More preferably,the viscosity of the carrier ranges from about 500 cps to about 7,000cps. The viscosity of the carrier of the present invention is measuredby using a Brookfield Viscometer having a # 3 spindle rotating at 20 rpmat 25° C.

The cores may comprise guanfacine in the form of powder, granules, andpellets. Alternatively, guanfacine may be layered over an inert particleto form a core.

Alternatively, guanfacine may be in the form of complex with a suitablecomplexing agent such as cyclodextrin or ion-exchange resins.

The core is in the form of a bead, a pellet, a granule, a spheroid, orthe like.

The term “inert particle,” as used herein, refers to a particle madefrom a sugar sphere also known as a non-pareil seed, a microcrystallinecellulose sphere, a dibasic calcium phosphate bead, a mannitol bead, asilica bead, a tartaric acid pellet, a wax based pellet, and the like.

Release-controlling agent may be mixed with guanfacine in the core.Alternatively, release-controlling agent may be coated over theguanfacine core. Alternatively, release-controlling agent may be presentboth in the core and as coating over guanfacine cores.

The release-controlling agent present in the core and/or as coating overthe core, is selected from the group comprising a pH-dependentrelease-controlling agent, a pH-independent release-controlling agent,or mixtures thereof.

Suitable examples of pH-dependent release-controlling agents areselected from the group comprising acrylic copolymers such asmethacrylic acid and methyl methacrylate copolymers, e.g., Eudragit® L100 and Eudragit® S 100, methacrylic acid and ethyl acrylate copolymers,e.g., Eudragit® L 100-55 and Eudragit® L 30 D-55, dimethylaminoethylmethacrylate and butyl methacrylate and methyl methacrylate copolymerse.g., Eudragit® E 100, Eudragit® E PO, methyl acrylate and methacrylicacid and octyl acrylate copolymers, styrene and acrylic acid copolymers,butyl acrylate and styrene and acrylic acid copolymers, andethylacrylate-methacrylic acid copolymer; cellulose acetate phthalate;cellulose acetate succinates; hydroxyalkyl cellulose phthalates such ashydroxypropylmethyl cellulose phthalate; hydroxyalkyl cellulose acetatesuccinates such as hydroxypropylmethyl cellulose acetate succinate;vinyl acetate phthalates; vinyl acetate succinate; cellulose acetatetrimelliate; polyvinyl derivatives such as polyvinyl acetate phthalate,polyvinyl alcohol phthalate, polyvinyl butylate phthalate, and polyvinylacetoacetal phthalate; zein; shellac; and mixtures thereof.

Suitable examples of pH-independent release-controlling agents areselected from the group comprising cellulosic polymers such as ethylcellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxyethylmethyl cellulose, hydroxypropylmethyl cellulose,cellulose acetate, and carboxy methylcellulose; acrylic copolymers suchas methacrylic acid copolymers, e.g., Eudragit® RS, Eudragit® RL,Eudragit® NE 30 D; polyethylene derivatives e.g., polyethylene glycoland polyethylene oxide; polyvinyl alcohol; polyvinyl acetate; gums e.g.,guar gum, locust bean gum, tragacanth, carrageenan, alginic acid, gumacacia, gum arabic, gellan gum, and xanthan gum; triglycerides; waxes,e.g., Compritol®, Lubritab®, and Gelucires®; lipids; fatty acids ortheir salts/derivatives; polyvinyl polymers; a mixture of polyvinylacetate and polyvinyl pyrrolidone, e.g., Kollidon® SR; and mixturesthereof. In particular, the pH-independent polymer used in the presentinvention is ethyl cellulose.

The cores of the present invention may additionally comprise one or moreof other pharmaceutically acceptable excipients selected from the groupcomprising acids, osmogents, binders, glidants, or combinations thereof.These have been defined above in the specification.

The diameter of the cores comprising guanfacine and arelease-controlling agent has a d₉₀ value of less than about 1.5 mm.More particularly, the d₉₀ value is less than about 1.2 mm. It isdesirable to keep the diameter of the cores within the specified size soas to avoid sedimentation of the cores, grittiness in the mouth andthereby rendering the composition more acceptable. The diameter of thecores is measured according to known methods, such as using Camsizer®.

As used herein, the term “d₉₀ value,” means at least 90% of the coreshave volume diameter in the specified range when measured by a suitablemethod, for example, Camsizer®.

The coating additives used in the present invention are selected fromthe group comprising plasticizers, opacifiers, anti-tacking agents,coloring agents, or combinations thereof.

Suitable plasticizers are selected from the group comprising triethylcitrate, dibutylsebacate, triacetin, acetylated triacetin, tributylcitrate, glyceryl tributyrate, diacetylated monoglyceride, rapeseed oil,olive oil, sesame oil, acetyl tributyl citrate, acetyl triethyl citrate,glycerin, sorbitol, diethyl oxalate, diethyl phthalate, diethyl malate,diethyl fumarate, dibutyl succinate, diethyl malonate, dioctylphthalate, and mixtures thereof.

Suitable opacifiers are selected from the group comprising titaniumdioxide, manganese dioxide, iron oxide, silicon dioxide, andcombinations thereof.

Suitable anti-tacking agents are selected from the group comprisingtalc, magnesium stearate, calcium stearate, stearic acid, silica,glyceryl monostearate, and mixtures thereof.

Suitable coloring agents are selected from the group consisting of FD&C(Federal Food, Drug and Cosmetic Act) approved coloring agents; naturalcoloring agents; natural juice concentrates; pigments such as ironoxide, titanium dioxide, and zinc oxide; and mixtures thereof.

Suitable solvents used for granulation or for forming a solution ordispersion for coating are selected from the group comprising water,ethanol, methylene chloride, isopropyl alcohol, acetone, methanol, andcombinations thereof.

The term “about,” as used herein, refers to any value which lies withinthe range defined by a variation of up to ±10% of the value.

The term “equivalent,” as used herein, refers to any value which lieswithin the range defined by a variation of up to ±30% of the value.

The term “significant leaching,” as used herein, means more than 20% ofthe guanfacine is leached out from the coated cores into the carrier.

The extended release liquid compositions of the present invention arehomogenous and delivers the desired dose of guanfacine in every usewithout any risk of overdosing or under dosing.

The amounts of each excipient can readily be determined or ascertainedby the person skilled in the art.

The invention also provides for methods of making the compositionsdescribed herein by usual methods well known in the art.

The cores of the present invention comprising guanfacine can be preparedby any method known in the art, e.g., extrusion-spheronization, wetgranulation, dry granulation, hot-melt extrusion granulation, spraydrying, and spray congealing. Alternatively, guanfacine can be layeredover an inert particle to form the core by conventional coatingprocesses.

Further, guanfacine can be directly coated with a release-controllingagent to form the microparticles or microcapsules. The microparticles ormicrocapsules can be prepared by a process of homogenization, solventevaporation, coacervation, phase separation, spray drying, spraycongealing, polymer precipitation, or supercritical fluid extraction.

Coating may be performed by applying the coating composition as asolution/suspension/ blend using any conventional coating techniqueknown in the art, such as spray coating in a conventional coating pan,fluidized bed processor, dip coating, or compression coating. Thepercentage of the coating build-up shall be varied depending on therequired extended release.

The process also includes forming complexes of guanfacine withion-exchange resins, comprising loading a plurality of resin particleswith guanfacine to form drug-resin particles. These particles mayoptionally be further coated with immediate release or extended releasecoating using conventional techniques. Methods of loading drugs ontoresin particles are generally known in the art.

The ready-to-use extended release liquid compositions of the presentinvention may be packaged in a suitable package such as a bottle. Thedry powder for reconstitution may be packaged in a suitable package suchas a bottle or a sachet. Further, the sachet can be filled as a unitdose or a multi dose sachet. The present invention further includes aco-package or a kit comprising two components, wherein one package orone component comprises a dry powder and another package or anothercomponent comprises the pharmaceutically acceptable carrier.Alternatively, a twin chamber pack with two chambers can be used. Inthis case, one chamber comprises a powder for suspension and anotherchamber comprises the carrier.

The invention also provides for various methods of treatment using thecompositions described herein. In a particular embodiment, the inventionprovides for methods of treating ADHD comprising administering aneffective amount of any of the composition described herein.

The invention may be further illustrated by the following examples,which are for illustrative purposes only and should not be construed aslimiting the scope of the invention in any way.

TABLE 1 pH dependent degradation profile (Guanfacinehydrochloride)-solution state stability Time % Assay (hours) pH 1.2 pH2.2 pH 4.5 pH 6.8 pH 7.5 0 101.2 100.3 99.4 99.5 100.9 1 101.2 100.599.0 99.0 99.9 4 101.2 100.4 98.7 97.2 97.1 8 101.1 100.4 98.9 93.7 92.216 101.6 100.3 98.7 86.3 84.0 24 101.4 100.2 98.5 79.9 77.5

As can be seen from the above Table 1, the assay values of guanfacineare substantially decreasing over time at high pH values, clearlyindicating decreased stability of guanfacine at high pH. On the otherhand, no major changes in assay values of guanfacine were observed inacidic conditions over time, indicating guanfacine is stable at lower pHvalues.

EXAMPLES 1-2 Comparative Compositions of Guanfacine

Quantity/unit (in mg) Example 2- Ingredients Example 1 ComparativeExample Guanfacine hydrochloride 1.15 1.15 Citric acid 1.40 0.00 Xylitol690.00 690.00 Water q.s. to 1 mL q.s. to 1 mLProcedure:

Guanfacine hydrochloride, xylitol, citric acid (in Example 1) were mixedin water to form liquid compositions.

Stability Studies

The compositions prepared as per Example 1 and Example 2 (ComparativeExample) were stored at room temperature and the samples were analyzedafter 3 days and 7 days. Stability results are represented in Table 2below.

TABLE 2 Stability data of compositions prepared as per Example 1 andExample 2 Impurities/Related Example 2- substances (RS) ICH Comparative(% w/w) Specification Example 1 Example 3 days- Room temperature2,6-Dichlorophenylacetic NMT 0.7 0.02 0.13 acid Highest Unknown ImpurityNMT 0.5 0.00 0.87 Total RS NMT 2.0 0.02 1.76 7 days- Room temperature2,6-Dichlorophenylacetic NMT 0.7 0.06 0.14 acid Highest Unknown ImpurityNMT 0.5 0.03 0.87 Total RS NMT 2.0 0.11 1.24

As seen from the above Table 2, it is observed that the amounts ofimpurity 2,6-dichlorophenyl acetic acid and total related substances wassignificantly reduced in composition having an acid as compared to thecomposition without an acid. Hence, it is clear that inclusion of anacid enhanced the stability of guanfacine.

EXAMPLES 3-5 Compositions of Guanfacine With Different Acids

Quantity/unit (in mg) Ingredients Example 3 Example 4 Example 5Guanfacine hydrochloride 1.15 1.1.5 1.15 Fumaric acid 3.5 — — Tartaricacid — 3.5 — Citric acid — — 3.5 Water q.s. to 1 mL q.s. to 1 mL q.s. to1 mLProcedure:

Guanfacine hydrochloride, suitable acid (fumaric/tartaric/citric acids)were mixed in water to form liquid compositions.

Stability Studies

The compositions prepared as per Examples 3-5 were stored at roomtemperature and the samples were analyzed after 30 days. Stabilityresults are represented in Table 3 below.

TABLE 3 Stability data of compositions prepared as per Examples 3-5Impurities/Related ICH Exam- Exam- Exam- substances (RS) Specifi- ple 3ple 4 ple 5 (% w/w) cation 30 days- Room temperature2,6-Dichlorophenylacetic NMT 0.7 0.23 0.22 0.27 acid Highest UnknownImpurity NMT 0.5 0.05 0.04 0.04 Total RS NMT 2.0 0.31 0.28 0.32

As seen from the above Table 3, equivalent stability results have beenobtained with all the three studied acids i.e. fumaric acid, tartaricacid and citric acid.

EXAMPLES 6-8 Guanfacine Extended Release Powder for SuspensionCompositions

Quantity/unit (in mg) Ingredients Example 6 Example 7 Example 8 Druglayered core Microcrystalline cellulose 30.00 30.00 30.00 spheresGuanfacine hydrochloride 1.15 1.15 1.15 Hydroxypropylmethyl cellulose4.00 4.00 4.00 Citric acid 0.02 0.2 0.50 Mannitol 3.00 3.00 3.00Purified water q.s. q.s. q.s. Extended release (ER) coated 35% w/w 35%w/w 44.26% w/w core coating coating coating Ethyl cellulose 12.02 12.0815.40 Dibutyl sebacate 1.33 1.34 1.71 Acetone q.s. q.s. q.s. Purifiedwater q.s. q.s. q.s. Weight of ER coated core 51.52 51.77 55.76 Carriercomposition Microcrystalline cellulose - 20.00 20.00 20.00 sodiumcarboxymethyl cellulose (Avicel ®CL-611) Xanthan gum 1.50 1.50 1.50Colloidal silicon dioxide 3.50 3.50 3.50 Sucralose 0.50 0.50 0.50Xylitol 450.00 450.00 450.00 Strawberry flavor 2.00 2.00 2.00 Citricacid 1.40 1.40 1.40 Methyl paraben — 1.80 1.80 Propyl paraben — 0.200.20 Purified water q.s. to q.s. to q.s. to 1 mL 1 mL 1 mLProcedure:

-   1. Citric acid, mannitol, hydroxypropylmethyl cellulose, guanfacine    hydrochloride were dissolved in purified water.-   2. Microcrystalline cellulose spheres were coated with the solution    of step 1.-   3. Ethyl cellulose and dibutyl sebacate were dispersed in a mixture    of acetone and purified water.-   4. The drug layered cores of step 2 were coated with the coating    dispersion of step 3 to form extended release powder for suspension.-   5. Microcrystalline cellulose-sodium carboxymethyl cellulose,    xanthan gum, colloidal silicon dioxide, sucralose, xylitol,    strawberry flavor, citric acid, methyl/propyl paraben (if present)    were mixed in purified water to form the pharmaceutically acceptable    carrier.-   6. The extended release powder for suspension and the    pharmaceutically acceptable carrier were separately packed in a twin    chamber pack.    Stability Studies

The extended release powder for suspension compositions prepared as perExamples 7 and 8 were stored at 40° C./75% RH for 3 months and 1 monthrespectively. Thereafter, the powder for suspension was reconstitutedwith the carrier and the amounts of impurity 2,6-dichlorophenyl aceticacid and total related substances was determined. The initial levels ofimpurities/related substances and levels after 3 months/1 month arerepresented in Table 4 below.

TABLE 4 Stability data of the reconstituted liquid compositions preparedas per Examples 7-8 Example 7 Example 8 Impurities/Related 40° C./ 40°C./ substances (RS) ICH 75% RH - 75% RH - (% w/w) Specification Initial3M Initial 1M 2-6 Dichlorophenyl NMT 0.7 0.03 0.22 0.00 0.06 acetic acidHighest Unknown NMT 0.5 0.05 0.03 0.03 0.02 Total RS NMT 2.0 0.14 0.340.03 0.08In-Vitro Studies

The extended release powder for suspension prepared as per Examples 6and 8 was reconstituted with the carrier and the in-vitro dissolutionwas determined for 4 mg dose at day 0 using USP type II apparatus at 75rpm, in 900 mL of hydrochloric acid buffer with pH 2.2 at 37° C. Theresults of the release studies are represented in Table 5.

TABLE 5 Percentage (%) of guanfacine release from reconstitutedcompositions prepared as per Examples 6 and 8 in 900 mL hydrochloricacid buffer pH 2.2, USP type II, 75 rpm Percentage (%) of guanfacinerelease Time (hours) Example 6 Example 8 1 18 11 2 38 29 4 58 54 6 68 6812 79 83 16 83 87 20 — 90 24 — 92

EXAMPLES 9-12 Guanfacine Extended Release Powder for SuspensionCompositions

Quantity/unit (in mg) Example Example Ingredients Example 9 10 Example11 12 Drug layered core Microcrystalline 30.00 30.00 30.00 30.00cellulose spheres Guanfacine 1.15 1.15 1.15 1.15 hydrochlorideHydroxypropylmethyl 4.00 4.00 4.00 4.00 cellulose Citric acid 0.50 0.500.50 0.50 Mannitol 3.00 3.00 3.00 3.00 Purified water q.s. q.s. q.s.q.s. Extended release 44.26% w/w coating (ER) coated core Ethylcellulose 15.4 15.4 15.4 15.4 Dibutyl sebacate 1.71 1.71 1.71 1.71Acetone q.s. q.s. q.s. q.s. Purified water q.s. q.s. q.s. q.s. Weight ofER 55.76 55.76 55.76 55.76 coated core Carrier composition Xylitol690.00 300.00 495.00 690.0 Citric acid 0.50 5.00 2.75 5.00 Purifiedwater q.s. to q.s. to q.s. to 1 mL q.s. to 1 mL 1 mL 1 mLProcedure:

-   1. Citric acid, mannitol, hydroxypropylmethyl cellulose, guanfacine    hydrochloride were dissolved in purified water.-   2. Microcrystalline cellulose spheres were coated with the solution    of step 1.-   3. Ethyl cellulose and dibutyl sebacate were dispersed in a mixture    of acetone and purified water.-   4. The drug layered cores of step 2 were coated with the coating    dispersion of step 3 to form extended release powder for suspension.-   5. Xylitol and citric acid were mixed in purified water to form the    pharmaceutically acceptable carrier.-   6. The extended release powder for suspension was reconstituted with    the pharmaceutically acceptable carrier and packed in a suitable    container.    Stability Studies

The compositions prepared as per Examples 9-12 were stored at roomtemperature for 30 days. After 30 days, the amounts of impurity2,6-dichlorophenyl acetic acid and total related substances wasdetermined. The results are represented in Table 6 below.

TABLE 6 Stability data of the reconstituted liquid compositions preparedas per Examples 9-12 Impurities/ Related ICH Exam- Exam- Exam- Exam-substances (RS) Speci- ple 9 ple 10 ple 11 ple 12 (% w/w) fication 30days- Room Temperature 2,6- NMT 0.7 0.11 0.13 0.12 0.09Dichlorophenylacetic acid Highest Unknown NMT 0.5 0.05 0.05 0.05 0.04Total RS NMT 2.0 0.16 0.18 0.17 0.13In-Vitro Studies

The powder for suspension compositions prepared as per Examples 9-11 wasstored for 10 days/30 days. After 10 days/30 days, the in-vitrodissolution was determined for 4 mg dose using USP type II apparatus at75 rpm, in 900 mL of hydrochloric acid buffer with pH 2.2 at 37° C. Theresults of the release studies are represented in Table 7 below.

TABLE 7 Percentage (%) of guanfacine release from reconstituted liquidcompositions prepared as per Examples 9-11 in hydrochloric acid bufferpH 2.2, USP type II, 75 rpm, 900 ml Percentage (%) of Guanfacine ReleaseExample 9 Example 10 Example 11 Time (hours) 10 days 30 days 10 days 30days 10 days 30 days 1 12 14 25 27 18 21 2 29 31 37 39 33 35 4 51 52 5556 54 55 6 65 65 67 68 67 67 12 83 82 83 83 84 83 16 88 87 88 88 88 8720 90 90 90 91 91 90 24 — 92 — 93 — 92

EXAMPLES 13-14 Guanfacine Extended Release Powder for SuspensionCompositions

Quantity/unit (in mg) Ingredients Example 13 Example 14 Drug Layeredcore Microcrystalline cellulose 30.00 30.00 spheres Guanfacinehydrochloride 1.15 1.15 Hydroxypropylmethyl cellulose 4.00 4.00 Citricacid 0.50 0.50 Mannitol 2.00 2.00 Purified water q.s. q.s. Extendedrelease (ER) coated 50% w/w coating 42.86% w/w coating core Ethylcellulose 16.94 14.52 Dibutyl sebacate 1.88 1.61 Acetone q.s. q.s.Purified water q.s. q.s. Weight of ER coated core 56.47 53.78 Carriercomposition Microcrystalline cellulose - 20.00 20.00 sodiumcarboxymethyl cellulose (Avicel ® CL-611) Xanthan gum 2.50 1.50Colloidal silicon dioxide 3.50 3.50 Sucralose 0.50 0.50 Xylitol 550.00550.00 Strawberry flavor 2.00 2.00 Citric acid 1.40 1.40 Methyl paraben1.80 1.80 Propyl paraben 0.20 0.20 Purified water q.s. to 1 mL q.s. to 1mLProcedure:

-   1. Citric acid, mannitol, hydroxypropyl methylcellulose, guanfacine    hydrochloride were dissolved in purified water.-   2. Microcrystalline cellulose spheres were coated with the solution    of step 1.-   3. Ethyl cellulose and dibutyl sebacate were dispersed in a mixture    of acetone and purified water.-   4. The drug layered cores of step 2 were coated with the coating    dispersion of step 3 to form extended release powder for suspension.-   5. Microcrystalline cellulose-sodium carboxymethyl cellulose,    xylitol, citric acid, xanthan gum, colloidal silicon dioxide,    sucralose, strawberry flavor, methyl paraben and propyl paraben were    mixed in purified water to form the pharmaceutically acceptable    carrier.-   6. The extended release powder for suspension and the    pharmaceutically acceptable carrier were separately packed in a twin    chamber pack.    Stability Studies

The extended release powder for suspension composition prepared as perExample 14 was stored at 40° C./75% RH for one month. After one month,the powder for suspension was reconstituted with the carrier and theamounts of impurity 2,6-dichlorophenyl acetic acid and total relatedsubstances was determined. The initial levels of impurities/relatedsubstances and levels after 1 month are represented in Table 8 below.

TABLE 8 Stability data of reconstituted liquid compositions prepared asper Example 14 Impurities/ Example 14 Related substances (RS) ICH 40°C./ (% w/w) Specification Initial 75% RH - 1 M 2-6 Dichlorophenyl aceticNMT 0.7 0.01 0.10 acid Highest Unknown NMT 0.5 0.03 0.03 Total RS NMT2.0 0.10 0.16In-Vitro Studies

The extended release powder for suspension prepared as per Example 14was stored at 40° C./75% RH for one month. After one month, the in-vitrodissolution was determined for 4 mg dose using USP type II apparatus at75 rpm, in 900 mL of hydrochloric acid buffer with pH 2.2 at 37° C. Theresults of the initial release studies and after 1 month are representedin Table 9 below.

TABLE 9 Percentage (%) of guanfacine release from extended releasepowder for suspension prepared as per Example 14 in 900 mL ofhydrochloric acid buffer, pH 2.2, USP type II, 75 rpm Percentage (%) ofguanfacine release Time (hours) Initial 40° C./75% RH - 1 M 1 19 22 2 3336 4 46 50 6 55 59 12 68 74 16 73 79 20 76 82 24 79 84Core Size Measurements

The sizes of the guanfacine layered cores and the extended releasecoated cores prepared as per Example 14 were measured by Camsizer andthe results are provided in Table 10 below:

TABLE 10 Core sizes Sample Core sizes Guanfacine layered core (withoutd₉₀ = 0.255 mm ER coating) d₅₀ = 0.187 mm d₁₀ = 0.141 mm Extendedrelease coated core d₉₀ = 0.349 mm d₅₀ = 0.239 mm d₁₀ = 0.181 mmViscosity Measurements

Viscosity of the carrier prepared as per Example 14 was measured byBrookfield viscometer. The values are provided in the Table 11 below.

TABLE 11 Viscosity measurements Sample Results Viscosity of the carrieras per Spindle 3 Example 14 rpm = 20 % torque = 18.1%, Viscosity = 905cpsOsmolality Measurements

Osmolality measurements for composition prepared as per Example 13 werecarried out using Osmomat 30D. Results are presented in the Table 12below:

TABLE 12 Osmolality measurements Name of Sample Osmolality (OSMOL/Kg)Guanfacine hydrochloride (API) (1 mg/mL) 0.006 Carrier 4.105 ER pelletcomposition (1 mg/unit) + vehicle 4.190 Final ER PFOS composition (1mg/mL) 4.025Osmolality Measurement of the External Phase

Xylitol, microcrystalline cellulose-sodium carboxymethyl cellulose,xanthan gum, strawberry flavor, sucralose, citric acid, methyl paraben,propyl paraben and colloidal silicon dioxide, purified water were mixedas per Example 13. This suspension was then filtered and diluted withpurified water, and the osmolality of the external phase was measuredusing Osmomat 030-D.

Osmolality of the external phase/carrier was determined to be 4.105osmol/kg of the carrier.

Osmolality Measurement of the Internal Phase

Various solutions having various concentrations of sodium chloride wereprepared as per Examples (A)-(D). The osmolalities of these solutionswere measured using Osmomat 030-D.

Ingredient Example A Example B Example C Example D Sodium 30.00 60.00120.00 180.00 Chloride (mg) Purified q.s. to 1 mL q.s. to 1 mL q.s. to 1mL q.s. to 1 mL water Osmolality 0.910 1.787 3.574* 5.361* (osmol/kg)*Extrapolated using values of dilute solutions

Sodium chloride was dissolved in purified water as per Examples A-D. Theosmolality of these solutions were measured using Osmomat 030-D.

TABLE 13 Extended release coated cores for osmolality measurementsIngredients Quantity (mg) Drug layered core Guanfacine hydrochloride1.15 Microcrystalline cellulose spheres 4.00 Hydroxypropylmethylcellulose 30.00 Mannitol 10.00 Purified Water q.s. Extended Release (ER)coated core Ethyl cellulose 14.22 Dibutyl sebacate 1.58 Acetone q.s.Purified Water q.s. Weight of Extended release (ER) coated core 60.95

The coated cores for osmolality measurement of internal phase wereprepared as provided in above Table 13. These cores were dispersed indifferent solutions as per Examples A-D. These suspensions were kept forseven days at room temperature. After seven days, each suspension wasfiltered and diluted with purified water. These were then analyzed byusing HPLC for guanfacine content. The results are represented in Table14.

TABLE 14 Effect of Osmolality on Guanfacine Leaching Osmolality(Osmol/kg) of Example the solution Guanfacine Content (%) A 0.910 69.80B 1.787 8.90 C 3.574* 1.30 D 5.361* 0.30 *Extrapolated using values ofdilute solutions

From the above data, it is evident that the leaching of guanfacine fromthe coated cores into the solution was decreasing as the osmolality ofthe solution was increasing from Examples A-D. The leaching is found tobe significantly reduced from Example C onwards. The osmolality of thecomposition prepared according to Example C is considered to beosmolality of the internal phase.

Osmolality ratio is calculated to be 1.149.

EXAMPLE 15 Guanfacine Extended Release Powder for SuspensionCompositions

Ingredients Quantity/unit (in mg) Drug layered core Microcrystallinecellulose spheres 30.00 Guanfacine hydrochloride 1.15 Citric acid 0.50Eudragit ®L 100-55 1.50 Triethyl citrate 0.15 Talc 0.45 Acetone q.s.Purified water q.s. Extended release (ER) coated core 15% w/w coatingEthyl cellulose 4.56 Dibutyl sebacate 0.51 Acetone q.s. Purified waterq.s. Weight of ER coated core 38.82 Carrier composition Microcrystallinecellulose - sodium 40.00 carboxymethyl cellulose (Avicel ® CL-611)Xanthan gum 2.50 Aerosil 3.50 Sucralose 0.50 Xylitol 550.00 Strawberryflavor 2.00 Citric acid 1.40 Methyl paraben 1.80 Propyl paraben 0.20Purified water q.s. to 1 mLProcedure:

-   1. Citric acid, Eudragit L 100-55, triethyl citrate, talc,    guanfacine hydrochloride were dispersed in a mixture of acetone and    purified water.-   2. Microcrystalline cellulose spheres were coated with the    dispersion of step 1.-   3. Ethyl cellulose and dibutyl sebacate were dispersed in a mixture    of acetone and purified water.-   4. The drug layered cores of step 2 were coated with the coating    dispersion of step 3 to form extended release powder for suspension.-   5. Microcrystalline cellulose-sodium carboxymethyl cellulose,    xylitol, citric acid, xanthan gum, colloidal silicon dioxide,    sucralose, strawberry flavor, methyl paraben and propyl paraben were    mixed in purified water to form the pharmaceutically acceptable    carrier.-   6. The extended release powder for suspension and the    pharmaceutically acceptable carrier were separately packed in a twin    chamber pack.    Bioequivalence Study of Guanfacine Extended Release Powder for Oral    Suspension

The extended release liquid composition of Example 14 having aconcentration of 1 mg/mL was dosed in an amount equivalent to 4 mg ofguanfacine (Test product). This composition was compared with thecommercially available extended release tablet composition of guanfacine(Intuniv® 4 mg tablets) (Reference product).

Fifteen healthy adult volunteers were enrolled for the study andfourteen completed at least two periods. An open label, balanced,randomized, three treatment, three-period, three sequence, relativebioavailability study was carried out under fasting condition. Bloodsamples were collected at appropriate time intervals and plasmaconcentrations of guanfacine were determined. The study was monitored interms of AUC_(0→∞), AUC_(last), C_(max), T_(lag), T_(max) achieved withthe test product and reference product.

Tables 15 and 16 indicate the results of the study. It was observed thatthe extended release composition of the present invention isbioequivalent to marketed extended release tablet composition.

TABLE 15 Pharmacokinetic parameters of the composition prepared inExample 14 against reference product (Intuniv ®) Intuniv ®Pharmacokinetic Composition of Example 14 (Reference parameters (Testproduct) product) C_(max) (pg/mL) 2738.85 3205.70 T_(max) (hr) 5.00 5.50T_(lag) (hr) 0.07 0.00 AUC_(last) (hr * pg/mL) 75035.51 79154.19AUC_(0→∞) (hr * pg/mL) 77178.70 81092.95

TABLE 16 Relative bioavailability in fasting condition (T/R)Pharmacokinetic Parameters Ratio (%) 90% C.I. Intra Subject CV (%)C_(max) (ng/ml) 88.32 77.51-100.65 19.70 AUC_(last) (ng · hr/mL) 97.1784.15-112.19 21.73 AUC_(0→∞) (ng · hr/mL) 97.42 84.76-111.98 21.03

We claim:
 1. A stable extended release suspension composition comprisingguanfacine in an amount of 1 mg/ml comprising a) coated cores consistingof i. cores comprising guanfacine; and ii. coating comprisingpH-independent release controlling agent over the cores of i; b) apharmaceutically acceptable carrier wherein the guanfacine is notpresent as guanfacine-resin complex and not more than about 30% ofguanfacine is released from the composition after 1 hour when determinedby a dissolution method using USP type II apparatus at 75 rpm, in 900 mLof hydrochloric acid buffer with a pH of 2.2 at 37° C.
 2. The stableextended release suspension composition of claim 1, wherein thecomposition exhibits an area under the curve (AUC)_(last) ranging fromabout 32000 hr*pg/mL to about 180000 hr*pg/mL upon administration of a 4mg dose of guanfacine under fasting state.
 3. The stable extendedrelease suspension composition of claim 1, wherein the compositionexhibits C_(max) from about 1800 pg/mL to about 9000 pg/mL uponadministration of a 4 mg dose of guanfacine under fasting state.
 4. Thestable extended release suspension composition of claim 1, wherein thecomposition exhibits T_(max) from about 2 hours to about 10 hours, uponadministration of a 4 mg dose of guanfacine under fasting state.
 5. Thestable extended release suspension composition of claim 1, wherein thecomposition exhibits T_(lag) of less than about 2 hours, uponadministration of a 4 mg dose of guanfacine under fasting state.
 6. Thestable extended release suspension composition of claim 1, wherein thecomposition is characterized by having an in-vitro dissolution releaseprofile using USP type II apparatus at 75 rpm, in 900 mL of hydrochloricacid buffer with a pH of 2.2 at 37° C. as follows: i about 35% to about75% of guanfacine released after 4 hours, and; ii not less than about75% of guanfacine released after 24 hours.
 7. The stable extendedrelease suspension composition of claim 6, wherein the in-vitrodissolution release profile of the extended release liquid compositionupon storage for at least seven days remains substantially similar tothe initial in-vitro dissolution release profile.
 8. The stable extendedrelease suspension composition of claim 1, wherein the composition has apH of less than about 6.8.
 9. The stable extended release suspensioncomposition of claim 1, wherein the composition is a ready-to-use liquidcomposition or a reconstituted liquid composition.
 10. The stableextended release suspension composition of claim 1, wherein guanfacinemay be present in the core or layered over an inert particle to form acore.
 11. A stable extended release suspension composition of guanfacinein an amount of 1 mg/ml comprising a. coated cores consisting of: i.inert particles ii. drug layer comprising guanfacine over the inertparticle to form a core; and iii. coating comprising pH-independentrelease controlling agent over cores of ii; b) a pharmaceuticallyacceptable carrier wherein the guanfacine is not present asguanfacine-resin complex and not more than about 30% of guanfacine isreleased from the composition after 1 hour when determined by adissolution method using USP type II apparatus at 75 rpm, in 900 mL ofhydrochloric acid buffer with a pH of 2.2 at 37° C.
 12. The stableextended release suspension composition of claim 11, wherein thecomposition comprises less than about 1.0% w/w of 2,6-dichlorophenylacetic acid.
 13. The stable extended release suspension composition ofclaim 11, wherein the composition comprises less than about 3.0% w/w oftotal related substances.
 14. The stable extended release suspensioncomposition of claim 11, wherein the core further comprises one or morepharmaceutically acceptable excipients selected from the groupconsisting of acids, osmogents, binders, glidants, and combinationsthereof.
 15. The stable extended release suspension composition of claim11, wherein the carrier comprises one or more of liquid adjuvants andother pharmaceutically acceptable excipients.
 16. The stable extendedrelease suspension composition of claim 11, wherein the otherpharmaceutically acceptable excipients in the carrier are selected fromthe group comprising acids, osmogents, buffering agents, suspendingagents, glidants, sweetening agents, flavors, colorants, anti-cakingagents, wetting agents, preservatives, antioxidants, chelating agents,binders, viscosity modifiers, and combinations thereof.
 17. The stableextended release suspension of claim 11, wherein the composition ischaracterized by having an osmolality ratio of at least about
 1. 18. Thestable extended release suspension of claim 11, wherein thepharmaceutically acceptable carrier has an osmolality of about 1osmol/kg or more than about 1 osmol/kg of the pharmaceuticallyacceptable carrier.